This invention relates to a method of treating basal cell carcinoma with recombinant human alpha interferon by administering the interferon directly into the carcinoma lesion, i.e. intralesionally.
Basal cell carcinomas are the most common cutaneous neoplasms found in humans. The majority of the 500,000 new cases of nonmelanoma skin cancers each year are basal cell carcinomas.
Basal cell carcinomas exist in a variety of clinical and histological forms such as nodular-ulcerative, superficial, pigmented, morphealike, fibroepithelioma and nevoid syndrome. Present treatment methods include various surgical techniques such as electrodesiccation and curettage, excision, cryosurgery and irradiation. Cure rates for the surgical techniques are generally stated to be about 95%. Despite the high cure rates effected by surgical techniques, non-surgical methods of therapy are generally thought to be more desirable.
Various efforts have been made to treat cancers by injecting interferon directly into the lesion. For example, Ikeda, Gan to Kagaku Ryoho, 12(4), 936-942 (1985) used recombinant interferon A to treat various malignant skin tumors and achieved low cure rates. None of the tumors treated were stated to be basal cell carcinomas. Sikora, K. (Editor), Interferon and Cancer, Ikic, D., Intralesional Therapy, 169-181, Plenum, N.Y. (1983) used unpurified human leukocyte interferon to treat basal cell carcinoma patients intralesionally. Ikic did not use a purified interferon material, but used a material containing a mixture of leukocyte interferon components and non-interferon impurities.
Barenbein, et al., Vestn. Dermatol. Venerol. No. (4): 31-33 (1985) used a "new Soviet interferon preparation, human leukocyte interferon for injection II" to treat skin basal cell carcinoma. It is not clear from the article if the "new" interferon is a recombinant human alpha interferon. The duration of the course of treatment varied from 10 to 20 days with a maximum dose of 100,000 International Units. The patients were injected twice daily for ten days, in a dose of 2,500-5,000 International Units, until a total dose of 50,000-100,000 IU was reached. This dosage is different than required to achieve the results of the present invention. Ikic et al., The Lancet, May 9, 1981, pp. 1025-1027, discloses local administration of crude leukocyte interferon to cancer patients, including those with basal cell carcinoma. Langer et al., Journal of Investigative Dermatology, 83, 128s-136s (1984) discloses purification, bacterial expression and biological activities of human interferons. Langer et al. state "Subsequent work has demonstrated that there are at least 10 highly related human alpha interferons (IFN-.alpha.) each with characteristic chemical and biological properties and each encoded by a different gene". In a discussion of leukocyte interferons, Langer et al. on page 130s stated:
"The purification of naturally induced human leukocyte interferons conclusively established several concepts; (1) Multiple leukocyte interferon species can be induced simultaneously in cultured human cells. This immediately suggested the existence of multiple genes corresponding to each of these structurally distinct species. (2) These interferons are closely related, having similar, but not identical molecular weights, amino acid content, and cryptic maps. (3) Although all the species were active on both human and bovine cells, the relative specific activities, particularly on human cells, differed considerably. (4) No carbohydrate was detected on five of the purified species examined. This contradicted the previously accepted notion that all interferons were glycoproteins." PA0 "If the various effects of interferon--antiviral, antiproliferative, natural killer cell activation, etc.--were all mediated through the same biochemical pathway, then it might be expected that the potency of a species in one assay would correlate with its potency in another assay. However, this was not observed."
and noted that the leukocyte interferons had different activities: "It was found that all the species exhibited antiproliferative activity on these cells [human lymphoblastoid Daudi cell line], although their potencies differed. This supported the notion that the chemical differences of the leukocyte interferon species are reflected in functional differences."
Langer et al. further observed that:
There is no discussion in Langer et al. regarding treatment of basal cell carcinoma. Staehelin et al., Methods in Enzymology, Pestka ed., 78, 505,511(1981), published prior to Langer et al. supra, discusses a homogeneous human leukocyte prepared from bacterial fermentations. The authors state: "The recombinant IFLrA exhibits antiviral activity and antiproliferative activity comparable to crude and purified natural leukocyte interferons." The identity of the species of interferon is not apparent, so it cannot be ascertained which of the numerous leukocyte interferon species is being discussed. There is no discussion of treatment of basal cell carcinoma.
Weissman, U.S. Pat. No. 4,530,901 discloses a means to make leukocyte type interferons with recombinant DNA molecules.
Interferons are a family of proteins which exhibit antiviral activity against certain viruses and anticancer activity against certain cancers. There are three types of interferons; alpha or leukocyte interferon, beta or fibroblast interferon and gamma or immune interferon. Human alpha interferon is a naturally occurring mixture of at least eleven components including those designated alpha-1 interferon and alpha-2 interferon. Human alpha interferon exhibiting biological properties similar to those of naturally occurring human leukocyte interferon can be made by recombinant methods.
A number of alpha interferon species or components are known and are usually designated by a numeral after the Greek letter alpha, and all are contemplated for use in this invention. Thus, the species designated human alpha-1 interferon and human alpha-2 interferon (sometimes called human alpha-2 interferon which includes human alpha-2a and human alpha-2b interferon; USAN: Interferon Alfa-2 including Interferon Alfa-2a and Interferon Alfa-2b) are contemplated, with human alpha-2 interferon preferred and Interferon Alfa-2b most preferred. Interferon alfa-2 can be produced in bacteria using recombinant techniques as disclosed in Rubenstein, Biochem. Biophys. Acta, 695, 5-6 (1982). In addition, interferon alfa-2 may be prepared by recombinant-DNA methods disclosed by Nagata et al., Nature, 284, 316-320 (1980), European Patent 32,134 and U.S. Pat. No. 4,289,690. Various alpha-2-interferon species are disclosed in U.S. Pat. No. 4,503,035. Preferred for use in this invention is purified human recombinant DNA interferon alfa-2b.